Abstract
Ca2+ influx via GluR2-lacking Ca2+-permeable AMPA glutamate receptors (CP-AMPARs) can trigger changes in synaptic efficacy in both interneurons and principle neurons, but the underlying mechanisms remain unknown. We took advantage of genetically altered mice with no or reduced GluR2, thus allowing the expression of synaptic CP-AMPARs, to investigate the molecular signaling process during CP-AMPAR-induced synaptic plasticity at CA1 synapses in the hippocampus. Utilizing electrophysiological techniques, we demonstrated that these receptors were capable of inducing numerous forms of long-term potentiation (referred to as CP-AMPAR dependent LTP) through a number of different induction protocols, including high-frequency stimulation (HFS) and theta-burst stimulation (TBS). This included a previously undemonstrated form of protein-synthesis dependent late-LTP (L-LTP) at CA1 synapses that is NMDA-receptor independent. This form of plasticity was completely blocked by the selective CP-AMPAR inhibitor IEM-1460, and found to be dependent on postsynaptic Ca2+ ions through calcium chelator (BAPTA) studies. Surprisingly, Ca/CaM-dependent kinase II (CaMKII), the key protein kinase that is indispensable for NMDA-receptor dependent LTP at CA1 synapses appeared to be not required for the induction of CP-AMPAR dependent LTP due to the lack of effect of two separate pharmacological inhibitors (KN-62 and staurosporine) on this form of potentiation. Both KN-62 and staurosporine strongly inhibited NMDA-receptor dependent LTP in control studies. In contrast, inhibitors for PI3-kinase (LY294002 and wortmannin) or the MAPK cascade (PD98059 and U0126) significantly attenuated this CP-AMPAR-dependent LTP. Similarly, postsynaptic infusion of tetanus toxin (TeTx) light chain, an inhibitor of exocytosis, also had a significant inhibitory effect on this form of LTP. These results suggest that distinct synaptic signaling underlies GluR2-lacking CP-AMPAR-dependent LTP, and reinforces the recent notions that CP-AMPARs are important facilitators of synaptic plasticity in the brain.
Highlights
The a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype glutamate receptors are the principal mediators of the fast excitatory synaptic transmission in the mammalian CNS and are important for the expression of various forms of longlasting synaptic plasticity, including long-term potentition (LTP) [1,2,3]
CP-AMPA receptors (AMPARs)-dependent LTP at CA1 synapses We have previously demonstrated that GluR2 mutants exhibit high Ca2+ permeability and inward rectification as well as an enhanced form of plasticity at CA1 synapses facilitated by Ca2+ influx through both NMDARs and CP-AMPARs [10,30]
Long-lasting L-LTP was clearly generated in GluR2+/ 2mice in the presence of 100 mM D,L-AP5 (14966.2%; P,0.001). This CP-AMPAR dependent L-LTP shared the characteristic dependence of longer-lasting forms of plasticity on the formation of new proteins [31], where plasticity induced in both wild-type and GluR2+/2slices (D,L-AP5+vehicle = 163610.8%; D,L-AP5+anisomycin = 10667.3%; P = 0.002) was significantly reduced (Figure 2C,D) under the administration of the protein synthesis inhibitor anisomycin (25 mM)
Summary
The a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype glutamate receptors are the principal mediators of the fast excitatory synaptic transmission in the mammalian CNS and are important for the expression of various forms of longlasting synaptic plasticity, including long-term potentition (LTP) [1,2,3]. AMPARs lacking edited GluR2 are Ca2+ permeable (CP-AMPAR) with higher conductance and inwardly rectifying I/V relationships. These GluR2-lacking CP-AMPARs are widely expressed in the CNS (including interneurons, stellate and glial cells) where they can contribute to synaptic transmission and changes in synaptic efficacy [8] as well as induce multiple forms of synaptic plasticity, including LTP [9,10,11,12,13,14,15]. CP-AMPARs are believed to play a crucial role in an unusual form of anti-Hebbian LTP [18]
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